Injuries or diseases that kill retinal neurons and receptors block vision at it source. The lack of effective repair in the retina is a hallmark of the human nervous system; neurons that die are not replaced and functions that are lost are not recovered. This bleak outcome is a driving force for research on neural stem cells and the field of regeneration biology. The long-term objective of the project described in this proposal is to elucidate the molecular mechanisms that regulate persistent neurogenesis and injury-induced neuronal and photoreceptor regeneration in the retinas of teleost fish. The teleost retina is the only vertebrate CMS tissue where stem cells can regenerate a single neuronal type that integrates into an existing circuit or can regenerate all cell types that completely restore the original tissue. Investigating stem cell-based regeneration in the teleost retina will advance our knowledge of mechanisms that govern the ability of intrinsic stem cells to restore neural circuits in the injured brain. Further, this knowledge may guide the development of potential stem cell-based therapies to treat nervous system injuries and disease. In this proposal three Specific Aims are described, each directed toward revealing molecular mechanisms that regulate the differentiation, genesis and regeneration of photoreceptors. In Specific Aim 1 experiments are described to test the hypothesis: that dying photoreceptors are transcriptionally active and express proteins that stimulate regeneration. In Specific Aim 2 reverse genetic approaches will be used to test the hypothesis that the bHLH transcription factor, neuroD, regulates cone differentiation and the proliferation of rod progenitors. In Specific Aim 3 the cellular expression of the growth factor progranulin-A will be characterized in the developing and regenerating retina, and reverse genetics will be used to test the hypothesis that progranulin-A regulates retinal neurogenesis. Together these specific aims represent a focused and integrated research program to test specific hypotheses of the cellular and molecular regulation of persistent arid injury-induced neurogenesis in the vertebrate nervous system. [unreadable] [unreadable]